US5157143A - Diastereoselective process for the preparation of intermediates useful for the synthesis of peptide derivatives - Google Patents
Diastereoselective process for the preparation of intermediates useful for the synthesis of peptide derivatives Download PDFInfo
- Publication number
- US5157143A US5157143A US07/350,462 US35046289A US5157143A US 5157143 A US5157143 A US 5157143A US 35046289 A US35046289 A US 35046289A US 5157143 A US5157143 A US 5157143A
- Authority
- US
- United States
- Prior art keywords
- formula
- phenyl
- temperature
- benzyloxycarbonylamino
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000000543 intermediate Substances 0.000 title abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title abstract description 9
- 108090000765 processed proteins & peptides Proteins 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 15
- -1 C1 -C6 alkyl Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- LCHWKMAWSZDQRD-UHFFFAOYSA-N silylformonitrile Chemical compound [SiH3]C#N LCHWKMAWSZDQRD-UHFFFAOYSA-N 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 230000009466 transformation Effects 0.000 claims description 3
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- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- OSALWGXOGJQCSU-UHFFFAOYSA-N triphenylsilylformonitrile Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C#N)C1=CC=CC=C1 OSALWGXOGJQCSU-UHFFFAOYSA-N 0.000 claims description 2
- CHLHGILFWIGSMM-UHFFFAOYSA-N tripropylsilylformonitrile Chemical compound CCC[Si](CCC)(CCC)C#N CHLHGILFWIGSMM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 101150108015 STR6 gene Proteins 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
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- 239000012074 organic phase Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
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- 239000002904 solvent Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
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- 239000003480 eluent Substances 0.000 description 6
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- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- LYNUWPBDPHNCGM-IAGOWNOFSA-N benzyl n-[(1s,2r)-1-cyano-1-hydroxy-3-phenylpropan-2-yl]carbamate Chemical compound C([C@H]([C@@H](C#N)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 LYNUWPBDPHNCGM-IAGOWNOFSA-N 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229950009811 ubenimex Drugs 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- JOIRXDZITUWREF-CVEARBPZSA-N benzyl n-[(2r,3s)-4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl]carbamate Chemical compound C([C@H]([C@H](O)C(=O)N)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 JOIRXDZITUWREF-CVEARBPZSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- OXBHRTLRTAHPNT-SJORKVTESA-N (2s,3r)-2-hydroxy-4-(4-methylsulfonylphenyl)-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C[C@H]([C@H](O)C(O)=O)NC(=O)OCC1=CC=CC=C1 OXBHRTLRTAHPNT-SJORKVTESA-N 0.000 description 3
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VKPAFUUERAKGHU-MRXNPFEDSA-N benzyl n-[(2r)-1-(4-methylsulfanylphenyl)-3-oxopropan-2-yl]carbamate Chemical compound C1=CC(SC)=CC=C1C[C@H](C=O)NC(=O)OCC1=CC=CC=C1 VKPAFUUERAKGHU-MRXNPFEDSA-N 0.000 description 3
- UGIMCNPWEAWMMT-MRXNPFEDSA-N benzyl n-[(2r)-1-(4-methylsulfonylphenyl)-3-oxopropan-2-yl]carbamate Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C[C@H](C=O)NC(=O)OCC1=CC=CC=C1 UGIMCNPWEAWMMT-MRXNPFEDSA-N 0.000 description 3
- NSXWJWLWAQOXLP-MRXNPFEDSA-N benzyl n-[(2r)-1-hydroxy-3-(4-methylsulfanylphenyl)propan-2-yl]carbamate Chemical compound C1=CC(SC)=CC=C1C[C@H](CO)NC(=O)OCC1=CC=CC=C1 NSXWJWLWAQOXLP-MRXNPFEDSA-N 0.000 description 3
- OLGGXXNDMFVDBG-MRXNPFEDSA-N benzyl n-[(2r)-1-hydroxy-3-(4-methylsulfonylphenyl)propan-2-yl]carbamate Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C[C@H](CO)NC(=O)OCC1=CC=CC=C1 OLGGXXNDMFVDBG-MRXNPFEDSA-N 0.000 description 3
- XQSDYVQUSAZHLD-SJORKVTESA-N benzyl n-[(2r,3s)-4-amino-3-hydroxy-1-(4-methylsulfonylphenyl)-4-oxobutan-2-yl]carbamate Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C[C@H]([C@H](O)C(N)=O)NC(=O)OCC1=CC=CC=C1 XQSDYVQUSAZHLD-SJORKVTESA-N 0.000 description 3
- VZBBBEKZTRKXGX-UHFFFAOYSA-N benzyl n-[1-cyano-1-hydroxy-3-(4-methylsulfanylphenyl)propan-2-yl]carbamate Chemical compound C1=CC(SC)=CC=C1CC(C(O)C#N)NC(=O)OCC1=CC=CC=C1 VZBBBEKZTRKXGX-UHFFFAOYSA-N 0.000 description 3
- KLRWBIHSTLAKRZ-UHFFFAOYSA-N benzyl n-[1-cyano-1-hydroxy-3-(4-methylsulfonylphenyl)propan-2-yl]carbamate Chemical compound C1=CC(S(=O)(=O)C)=CC=C1CC(C(O)C#N)NC(=O)OCC1=CC=CC=C1 KLRWBIHSTLAKRZ-UHFFFAOYSA-N 0.000 description 3
- QMLOCVSLQRKAJY-MSOLQXFVSA-N methyl (2s,3r)-2-hydroxy-4-(4-methylsulfanylphenyl)-3-(phenylmethoxycarbonylamino)butanoate Chemical compound C([C@H]([C@H](O)C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(SC)C=C1 QMLOCVSLQRKAJY-MSOLQXFVSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- OXBHRTLRTAHPNT-DLBZAZTESA-N (2r,3s)-2-hydroxy-4-(4-methylsulfonylphenyl)-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C[C@@H]([C@@H](O)C(O)=O)NC(=O)OCC1=CC=CC=C1 OXBHRTLRTAHPNT-DLBZAZTESA-N 0.000 description 2
- AMUPAYRNPWRZOX-SCZZXKLOSA-N (2s,3r)-2-hydroxy-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound OC(=O)[C@@H](O)[C@@H](C)NC(=O)OCC1=CC=CC=C1 AMUPAYRNPWRZOX-SCZZXKLOSA-N 0.000 description 2
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- 125000003440 L-leucyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 2
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
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- 125000005843 halogen group Chemical group 0.000 description 2
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- LWUQALZULRYDPC-UHFFFAOYSA-N 2H-benzotriazole-4,5-diol Chemical compound OC1=CC=C2NN=NC2=C1O LWUQALZULRYDPC-UHFFFAOYSA-N 0.000 description 1
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- 102100032126 Aminopeptidase B Human genes 0.000 description 1
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- 239000002841 Lewis acid Substances 0.000 description 1
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- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/43—Y being a hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
Definitions
- the present invention relates to a diastereoselective process for the preparation of intermediates useful for the synthesis of peptide derivatives and, more particularly, it relates to a diastereoselective process for the preparation of N-protected derivatives of 3-amino-4-aryl-2-hydroxy-butanoic acid of formula ##STR2## wherein R represents a phenyl optionally substituted by from 1 to 3 substituents selected among hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, phenyl, amino, mono or dialkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, nitro, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl groups having from 1 to 6 carbon atoms in the alkyl moiety;
- R 1 represents a protecting group and the asterisks show the asymmetric carbon atoms
- Bestatin Drugs of the Future, vol. VI, no. 10 (1981), page 604] the compounds showing an inhibitory activity on aminopeptidase B described in British Patent no. 1 510 477 and in U.S. Pat. No. 4,185,156 (Microbiochemical Research Foundation) and in the Italian patent application no. 19791 A/88 (Zambon Group S.p.A.), the anti-hypertensive compounds described in U.S. Pat. No. 4,293,481 (Squibb E. R. and Sons, Inc.) or the analgesic compounds described in the Japanese patent application no. 60/248659 (Microbiochemical Research Foundation).
- Each of them comprises the optical resolution of a racemic mixture, which is carried out on the compound of formula II or on an intermediate of the synthesis, such as for example a compound of formula I, in order to separate the diastereoisomer with the desired configuration.
- optical resolution of diastereoisomeric salts obtained using optically active bases such as brucine (British Patent no. 1 510 477), alpha-phenylethylamine (Japanese patent application no. 58/41848--Nippon Kayaku Co. Ltd.) and S(-)-alpha-methylbenzylamine [J. Antib., 36(6), 1983, 695].
- optically active bases such as brucine (British Patent no. 1 510 477), alpha-phenylethylamine (Japanese patent application no. 58/41848--Nippon Kayaku Co. Ltd.) and S(-)-alpha-methylbenzylamine [J. Antib., 36(6), 1983, 695].
- the separation is carried out also by chromatographic methods [J. Antib., 29(5), 1976, 600].
- the aldehyde of formula V is obtained by subsequent oxidation.
- the compounds of formula III are known (European patent application no. 167 459 in the name of Albert Rolland S.A.) or they are easily prepared by known methods.
- the protection of the amino function in order to obtain the compounds of formula IV is carried out according to usual technqiues in organic chemistry, especially in peptide chemistry, by reaction of a compound of formula III with a compound of formula R 1 X wherein R 1 is a protecting group and X represents a halogen atom.
- halides of carbonic acid esters are used as protecting agents of formula R 1 X.
- Suitable protecting groups (R 1 ) are adamantyloxycarbonyl, t.amyloxycarbonyl, benzhydryloxycarbonyl, benzyloxycarbonyl, p.bromobenzyloxycarbonyl, t.butoxycarbonyl, cyclohexyloxycarbonyl, cyclopentyloxycarbonyl, p.methoxybenzyloxycarbonyl, p.nitrobenzyloxycarbonyl, p.phenylazobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl.
- Preferred protecting groups are benzyloxycarbonyl and t.butoxycarbonyl.
- the protected aminoalcohol of formula IV is then oxidized in order to obtain the corresponding aldehyde of formula V.
- the preferred oxidizing agent for its better availability and cost is dimethylsulfoxide which is used optionally in the presence of other reagents such as SO 3 -pyridine-triethylamine complex, tosyl chloride, acetic anhydride or, preferably, oxalyl chloride and triethylamine, in an inert organic solvent.
- the step of transformation of the aldehyde V in the cyanohydrin VI which by itself is a further object of the present invention, is carried out by reaction with a suitable silylcyanide in an aprotic solvent at a temperature between -80° C. and room temperature.
- the reaction may be optionally carried out in the presence of suitable catalysts such as Lewis acids, for example zinc iodide, zinc chloride, titanium tetrachloride and stannic chloride or such as alkaline cyanides, for example potassium cyanide or its compounds with crown ethers, and sodium cyanide.
- suitable catalysts such as Lewis acids, for example zinc iodide, zinc chloride, titanium tetrachloride and stannic chloride or such as alkaline cyanides, for example potassium cyanide or its compounds with crown ethers, and sodium cyanide.
- silylcyanides which may be optionally prepared in situ from the corresponding silylchlorides with potassium cyanide, are trimethylsilylcyanide, triphenylsilylcyanide, phenyldimethylsilylcyanide, ethyldimethylsilylcyanide, t.butyldimethylsilylcyanide, tripropylsilylcyanide.
- Suitable aprotic solvents there are aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform, methylene chloride and dichloroethane, ethers such as ethyl ether, tetrahydrofuran, dioxane, isopropyl ether and t.butylmethylether.
- aromatic hydrocarbons such as benzene and toluene
- halogenated hydrocarbons such as chloroform, methylene chloride and dichloroethane
- ethers such as ethyl ether, tetrahydrofuran, dioxane, isopropyl ether and t.butylmethylether.
- the reaction is carried out with trimethylsilylcyanide at a temperature between -80° C. and -20° C.
- the reaction of formation of the cyanohydrin starting from the aldehyde V is diastereoselective.
- the second asymmetric center is introduced by the reaction of formation of the cyanohydrin.
- this reaction of the process object of the present invention acts diastereoselectively giving prevailingly the cyanohydrin VI wherein the carbon atom bearing the hydroxy group has S configuration.
- the diastereoisomerically pure cyanohydrin VI may be obtained by simple crystallization or suspension in a suitable solvent of the mixture of the two diastereoisomers obtained by the process object of the present invention.
- the hydrolysis is carried out in an acid environment with concentrated inorganic acids, preferably hydrochloric acid, mixed with an organic solvent and at a temperature between 0° C. and room temperature.
- concentrated inorganic acids preferably hydrochloric acid
- the intermediate of formula VII is obtained as an amide (R 4 ⁇ NH 2 ) when the hydrolysis is carried out with an aqueous acid or, alternatively, as an ester (R 4 ⁇ C 1 --C 3 alkoxy) when the hydrolysis is carried out using an alcoholic solution of the inorganic acid.
- the intermediate VII is, then, further hydrolized to give the diastereoisomerically pure acid I using a diluted inorganic acid or base, at a temperature between 60° C. and the reflux temperature of the reaction mixture.
- hydrochloric acid or sodium hydroxide at 1N concentration are used.
- the aldehyde V in S configuration is, then, diastereoselectively transformed in a mixture of the two diastereoisomeric cyanohydrins (2R,3S) and (2S,3S) in which the (2R,3S) cyanohydrin VI highly prevails.
- the aldehyde V may be prepared in situ from the aminoalcohol IV and directly reacted in the same reaction environment with a suitable silylcyanide to obtain the cyanohydrin VI.
- the acid I may be, then, directly obtained by carrying out, for example, the acid hydrolysis first with a concentrated aqueous inorganic acid at room temperature for some hours and then, by diluting with water the reaction mixture, at the reflux temperature.
- a preferred embodiment of the process object of the present invention is the preparation of the intermediate of formula I wherein R represents an unsubstituted phenyl, useful for the synthesis of Bestatin.
- the acid of formula I (R phenyl), obtainable according to the process of the invention starting, for example, from the corresponding aminoalcohol of formula III wherein R represents a phenyl, is condensed with a derivative of L-leucine with the carboxy group protected as, for example, benzyl ester, in the presence of condensing agents such as dicyclohexylcarbodiimide and of dihydroxybenzotriazole.
- Bestatin may be carried out also starting from different aminoalcohols of formula III that is from aminoalcohols with substituents on the aromatic ring which are easily removable or which are easily transformable into removable groups.
- the corresponding unsubstituted derivatives may be obtained by reduction.
- the process object of the present invention has several advantages with respect to the known processes for the preparation of the acids of formula I.
- reaction mixture was kept under stirring for an hour at -70° C. and then, under the same conditions, a solution of trimethylsilylcyanide (20 ml; 0.154 moles) in methylene chloride (40 ml) was added dropwise.
- the reaction mixture was kept at -70° C. for 4 hours and then the temperature was allowed to arise very slowly (10-12 hours) up to the room value.
- Trimethylsilylcyanide (2.6 ml; 0.019 moles) was added dropwise, under stirring and at room temperature to a solution of (R)-2-benzyloxycarbonylamino-3-phenyl-propanal (4.6 g; 0.016 moles) in tetrahydrofuran (45 ml).
- reaction mixture was kept under stirring at room temperature for 30 minutes, then ethyl ether (50 ml) was added and the aqueous phase was saturated with sodium chloride.
- reaction mixture was kept under stirring at room temperature for 6 hours and, then, poured into water (5 l).
- the aqueous phase was extracted with ethyl acetate (1 l) and the collected organic phases were washed with 5% hydrochloric acid, with 5% sodium bicarbonate and with water.
- the temperature was left arising up to the room value and water (600 ml) was added.
- Trimethylsilylcyanide 25 ml; 0.20 moles was added dropwise to a suspension of (2R)-2-benzyloxycarbonylamino-3-(4-methylsulfonyl-phenyl)-propanal (69.4 g; 0.19 moles), prepared as described in example 7, in methylene chloride (1 l), under stirring and at room temperature.
- the pH was kept between 8 and 9.
- the aqueous phase was extracted with ethyl acetate (2 ⁇ 250 ml) and the collected organic phases were washed with a 5% hydrochloric acid solution and then with a 5% sodium bicarbonate solution. After drying on sodium sulphate, the solvent was evaporated under reduced pressure giving a crude (38 g) which was purified by chromatography on silica gel (70-230 mesh) using methylene chloride with a gradient of ethyl acetate as eluent.
- Trimethylsilylcyanide (10.17 ml; 0.081 moles) was added dropwise to a solution of (2R)-2-benzyloxycarbonylamino-3-(4-methylthiophenyl)-propanal (24 g; 0.073 moles), prepared as described in example 12, in methylene chloride (275 ml) keeping the reaction mixture under stirring at 0° C.
- the solution was concentrated by evaporating under reduced pressure, water (100 ml) and ethyl acetate (100 ml) were added, 10% hydrochloric acid was added up to pH 1 and the phases were separated.
- the solution was heated under reflux for 6 hours, colled to room temperature and then extracted with ethyl acetate (3 ⁇ 300 ml).
- the collected organic phases were treated with a 5% sodium bicarbonate solution (500 ml); the aqueous phase was separated, acidified with hydrochloric acid and extracted with ethyl acetate (2 ⁇ 300 ml).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT20542A/88 | 1988-05-11 | ||
IT20542/88A IT1217567B (it) | 1988-05-11 | 1988-05-11 | Processo diastereoselettivo per la preparazione di intermedi utili per la sintesi di derivati peptidici |
Publications (1)
Publication Number | Publication Date |
---|---|
US5157143A true US5157143A (en) | 1992-10-20 |
Family
ID=11168517
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/350,462 Expired - Fee Related US5157143A (en) | 1988-05-11 | 1989-05-11 | Diastereoselective process for the preparation of intermediates useful for the synthesis of peptide derivatives |
Country Status (8)
Country | Link |
---|---|
US (1) | US5157143A (ja) |
EP (1) | EP0341462B1 (ja) |
JP (1) | JP2860559B2 (ja) |
AT (1) | ATE80380T1 (ja) |
DE (1) | DE68902771T2 (ja) |
ES (1) | ES2052801T3 (ja) |
GR (1) | GR3006432T3 (ja) |
IT (1) | IT1217567B (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5648511A (en) * | 1990-11-19 | 1997-07-15 | G.D. Searle & Co. | Method for making intermediates useful in the synthesis of retroviral protease inhibitors |
US5900503A (en) * | 1996-02-08 | 1999-05-04 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active cyanohydrins |
US6743929B1 (en) | 1992-08-25 | 2004-06-01 | G. D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001048850A (ja) | 1999-05-28 | 2001-02-20 | Kanegafuchi Chem Ind Co Ltd | ノルスタチン誘導体の製造法 |
JP2002047256A (ja) * | 2000-07-26 | 2002-02-12 | Kanegafuchi Chem Ind Co Ltd | α−アミノ−α´,α´,α´−トリハロケトン誘導体、α−アミノ−α´,α´,α´−トリハロアルコ−ル誘導体、及び、α−ヒドロキシ−β−アミノカルボン酸誘導体の製造法 |
EP1942101A4 (en) | 2005-09-05 | 2010-08-25 | Yoshiaki Kiso | INHIBITOR OF -SECRETASE |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4281180A (en) * | 1978-11-25 | 1981-07-28 | Nippon Kayaku Kabushiki Kaisha | Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them |
US4352752A (en) * | 1980-03-07 | 1982-10-05 | Sagami Chemical Research Center | Process for the preparation of dipeptides |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS5936902B2 (ja) * | 1977-06-22 | 1984-09-06 | 財団法人微生物化学研究会 | (2s,3r)−3−アミノ−2−ヒドロキシ−4−p−ヒドロキシフエニルブタノイル−(s)−ロイシンおよびその製造法 |
-
1988
- 1988-05-11 IT IT20542/88A patent/IT1217567B/it active
-
1989
- 1989-04-20 EP EP89107141A patent/EP0341462B1/en not_active Expired - Lifetime
- 1989-04-20 AT AT89107141T patent/ATE80380T1/de active
- 1989-04-20 ES ES89107141T patent/ES2052801T3/es not_active Expired - Lifetime
- 1989-04-20 DE DE8989107141T patent/DE68902771T2/de not_active Expired - Fee Related
- 1989-05-11 US US07/350,462 patent/US5157143A/en not_active Expired - Fee Related
- 1989-05-11 JP JP1118483A patent/JP2860559B2/ja not_active Expired - Lifetime
-
1992
- 1992-12-02 GR GR920402796T patent/GR3006432T3/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4281180A (en) * | 1978-11-25 | 1981-07-28 | Nippon Kayaku Kabushiki Kaisha | Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them |
US4352752A (en) * | 1980-03-07 | 1982-10-05 | Sagami Chemical Research Center | Process for the preparation of dipeptides |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5648511A (en) * | 1990-11-19 | 1997-07-15 | G.D. Searle & Co. | Method for making intermediates useful in the synthesis of retroviral protease inhibitors |
US6743929B1 (en) | 1992-08-25 | 2004-06-01 | G. D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US20040267022A1 (en) * | 1992-08-25 | 2004-12-30 | G. D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US5900503A (en) * | 1996-02-08 | 1999-05-04 | Nippon Kayaku Kabushiki Kaisha | Process for producing optically active cyanohydrins |
Also Published As
Publication number | Publication date |
---|---|
ATE80380T1 (de) | 1992-09-15 |
DE68902771T2 (de) | 1993-01-07 |
JP2860559B2 (ja) | 1999-02-24 |
ES2052801T3 (es) | 1994-07-16 |
DE68902771D1 (de) | 1992-10-15 |
EP0341462B1 (en) | 1992-09-09 |
JPH0228144A (ja) | 1990-01-30 |
IT8820542A0 (it) | 1988-05-11 |
EP0341462A1 (en) | 1989-11-15 |
GR3006432T3 (ja) | 1993-06-21 |
IT1217567B (it) | 1990-03-30 |
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